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Funders:
The Wellcome Trust

Results

Optimising antimalarial combination therapies in an area coendemic for vivax and falciparum malaria 07 Jul 2015

I have established a large network of researchers, service providers, and policy makers in Papua, Indonesia to undertake a series of epidemiological, clinical, and laboratory studies to optimise the treatment and prevention of malaria. Previous studies led to a district-wide (population 180,000) change in policy for uncomplicated malaria to artemisinin combination therapy in 2006. The current proposal will expand our research agenda to address the next phase of ACT deployment, notably an underst anding of the co-factors that determine its impact and cost-effectiveness and how these differentially affect P. falciparum and P. vivax. Novel and complementary studies are planned to optimise the treatment of vivax relapses, improve the diagnosis of G6PD deficiency and develop genetic tools for monitoring drug resistance. This research will provide the evidence base upon which to optimise malaria control programmes. The crucial involvement of collaborative partners in the District Health Au thority, local government and Indonesian National CDC will ensure that the results of the project impact directly on MoH policy decisions not only for Papua but also elsewhere in Indonesia. My objective is that these tools will be endorsed by WHO and adopted by the current global elimination efforts.

Amount: £107,663
Funder: The Wellcome Trust
Recipient: University of Oxford

Senior Research Fellowship in Clinical Science 03 Dec 2014

This proposal will address the questions of whether microparticles of iron oxide can be used asreliable and conspicuous molecular probes for magnetic resonance imaging to (1) detect, inquantitative fashion, the endothelial expression of pro-inflammatory molecules, (2) identify featuresof subclinical disease that predict later disease burden and (3) quantify responses to treatmentthat are invisible to current imaging approaches. Further, we will evaluate, in comparative fashion,the binding characteristics of existing and novel ligands (including synthetic glycoproteins) and wewill establish the characteristics of our new generation of biodegradable iron rich microparticles forimaging.

Amount: £216,553
Funder: The Wellcome Trust
Recipient: University of Oxford

Understanding the biophysical basis of energy storage in adipocyte lipid droplets and the metabolic consequences of the failure of this process. 01 Apr 2015

My proposal hinges on the hypothesis that having evolved in a nutritionally challenging environment, humans are particularly well adapted to ensuring sufficient energy intake, but considerably less well adapted to coping with sustained access to energy dense foodstuffs. And that failure to optimally store surplus energy as neutral lipid within cytosolic lipid droplets (CLDs) in adipocytes, results in lipid accumulation in other tissues such as the liver where it plays a seminal role in causing i nsulin resistance, type 2 diabetes, fatty liver, dyslipidaemia and ultimately cardiovascular disease. The aim is therefore to deepen and broaden understanding of the molecular basis of lipid storage within CLDs as well as the physiological consequences of overload/failure of this process. The approach we have adopted is distinguished by being primarily based on studies involving patients with a rare disease characterised by a lack of body fat i.e. lipodystrophy. Paradoxically, lipodystrophy leads to severe manifestations of the same metabolic diseases typically associated with obesity. In both cases, we hypothesise that metabolic disease arises as a result of a mismatch between the need and capacity to store surplus energy in adipocytes. This mismatch is particularly extreme in lipodystrophy, providing a more tractable model in which to study the pathophysiology of this problem. Having made some important genetic discoveries recently, we are now seeking to address fundamental biol ogical questions which have emerged from our primary genetic discoveries, whilst also seeking to broaden our knowledge of the genetic basis of other rare adipose tissue diseases.

Amount: £1,487,351
Funder: The Wellcome Trust
Recipient: University of Cambridge

One year funding - Community-wide TB case-finding linked to a nested cluster-randomised trial of promotion of HIV-testing and prevention of HIV-rel ated TB 01 Apr 2015

The key goal is to identify a high impact strategy that could be used to achieve rapid reductions in TB incidence within a few years in high HIV prevalence urban setting. Two strategies will be investigated, first whether community-based case-finding alone can achieve this goal. An alternative possibility will be investigated through a parallel nested cluster-randomised trial: the additional impact of intensive prevention of HIV-related TB (promotion of HIV testing in the community linked t o isoniazid preventive therapy and referral for routine antiretroviral therapy). The same periodic outreach TB case-finding strategy that successfully reduced the prevalence of undiagnosed TB in Harare will be used, this time applied over a longer period (4 years) to a confluent population of 108,000 adults in order to capture the impact on TB transmission rates and new incident disease. Our community-based HIV/TB intervention will be delivered to 16,800 individual in the intervention arm of cluster randomised trial using local counsellors, including the option of supervised self-testing for HIV, and linked to community-distribution of isoniazid preventive therapy and referral for facility-based antiretroviral therapy. The key goals will be the effect on TB incidence, and acceptability and uptake of the HIV testing strategy.

From molecules to pandemics: multi-level adaptation of human chronic viruses. 27 May 2015

Chronic viruses, such as HIV and HCV, evolve rapidly within individuals. Combined with long durations of infection, this means transmitted strains will be different from founder strain(s) that initiate infections, which in turn will have large effects on these viruses at the epidemiological scale including: the rate of spread of transmitted drug resistance; adaptation to the HLA background of the host population; and the evolution of viral pathogenesis. I will determine how virus evolution withi n-hosts affects the epidemiology of chronic viruses and predict the consequences of these effects under different intervention scenarios. It is becoming increasingly apparent that the presence of viral reservoirs and compartmentalisation has qualitative effects on within-host viral evolution. I will fit mathematical models to next-generation sequencing data to establish whether this significantly delays within-host evolutionary dynamics in natural and drug treated infections, and whether vir al strains similar to founder strains are preferentially transmitted. Importantly, I will test whether we see the same patterns for different classes of mutations, such as immune and drug escape mutations. This will allow me to develop epidemiological models that integrate within-host and transmission processes and ask how this impacts the among-host evolution of chronic viral infections.

Amount: £753,548
Funder: The Wellcome Trust
Recipient: University of Oxford

Regulatory signalling networks between stem and niche cells in lung regeneration. 27 May 2015

For multipotent stem cells to properly orchestrate injury repair, it is necessary for signals to instruct stem cells to produce specialised cells that replace injured epithelia. The precise signals from the stromal/niche cells that can stimulate differentiation for lung injury repair are under-investigated. In this proposal, I will directly address gaps in the understanding of the regulation of stem cell lineage differentiation by characterising novel stromal cell populations expressing Lgr6 in the murine distal lung and their functional interactions with region-specific stem cells during injury repair. Aim 1 will define dynamics of Lgr6-expressing cells by tracking them in homeostasis and during injury repair. In vitro organoid co-culture of regional epithelial stem/progenitor cells with Lgr6+ cells will address functional interactions between epithelia and Lgr6+ stromal cells. I will also determine if Lgr6+ cells are essential for stem cell lineage differentiation in vivo. Aim 2 will further dissect regulatory signalling molecules derived from Lgr6+ cells. Gene expression profiling of Lgr6+ cells with regional epithelial cells will describe key signalling pathways that will be evaluated by in vitro organoid co-culture assay and by in vivo mouse genetics. This work will enhance our understanding of regulatory networks between stem-niche interactions in lung regeneration.

Amount: £1,226,049
Funder: The Wellcome Trust
Recipient: University of Cambridge

Characterization of inflammation driven responses in human hematopoietic stem and progenitor cells. 27 May 2015

The existence of functionally distinct haematopoietic stem cell (HSC) subsets is crucial for steady-state blood production and efficient recovery from injury. However, if and how these HSC subsets differentially respond to stress signals has not been addressed. Moreover, some HSC stress responses have been shown to be species-specific, underlining the necessity of studying human cells directly. My own transcriptional profiling of highly purified human long-term (LT-) and short-term (ST-) HSC ind icates that these HSC subsets may be differentially sensitive to a range of pro-inflammatory signals. As a handful of inflammation cues are known to directly affect HSC or progenitor cell function during development and infection, my specific objectives are to: 1) identify novel pro-inflammatory signals that act directly on human HSC subsets; 2) define how they alter HSC function; 3) determine through which molecular mechanisms this happens. This candidate-identification approach carried out on cells from healthy donors will be complemented with a comprehensive characterization of the inflammatory milieu, functional responses and transcriptional profiles of HSC and progenitor cells isolated from patients with chronic inflammatory diseases. Altogether, I expect these studies to provide new insights on the impact of inflammation on HSC biology and its contribution to disease.

Amount: £1,245,529
Funder: The Wellcome Trust
Recipient: University of Cambridge

Natural killer cell subsets in the liver: phenotype, function and role in obesity-induced liver disease. 29 Oct 2014

Organ-specific natural killer (NK) cells form a distinct lineage from their circulating counterparts and have specialist physiological functions. In the last year, a liver-specific NK subset has been identified in mice. Whether an equivalent population exists in human liver is not yet known, nor is the function of these cells known in either humans or mice. My goal is to address these questions with specific reference to NASH. I will examine liver transplant perfusates by flow cytometry for the transcription factors that define the liver-specific NK subset, and for relevant surface markers. I will then investigate whether any of the subsets identified are liver-specific using in vitro lymphocyte differentiation assays and by comparing their representation in donor- versus recipient-derived NK cells from explanted livers. I will perform ex vivo assays for expected functions such as cytokine production and cytotoxicity. Microarray analysis will also be used to identify any novel function s. Using marginal tissue from liver resections, I will determine whether NK subset frequency and function differs between NASH livers and controls. To test the hypothesis that liver-specific NK cells affect the progression of NASH, I will examine disease severity in Tbx21[fl/fl]Ncr1[icre] mice, which specifically lack these cells.

Amount: £782,599
Funder: The Wellcome Trust
Recipient: University College London

Investigating the spatiotemporal regulation of microtubule nucleation in Drosophila. 29 Oct 2014

Microtubules are dynamic polymers that have crucial roles in many eukaryotic cell processes. They are nucleated by multi-protein gamma-TuRCs that are concentrated at various MTOCs within the cell. Although most, if not all, of the gamma-TuRC components are known, it remains unclear how gamma-TuRCs are recruited to different MTOCs at different times during development and during the cell cycle. Moreover, it is not clear how each component functions in the complex. Previous studies have concentrat ed on specific gamma-TuRC components or cell types, and have often studied only mitotic processes. I will use Drosophila as a model to conduct a comprehensive in vivo analysis of gamma-TuRC biology in various cell types, including mitotic cells, developing oocytes and terminally differentiated neurons. Mutant and fluorescently tagged lines exist for most, but not all, of the gamma-TuRC components and I intend to complete this toolset using CRISPR, a novel and rapid genome engineering technique t hat works very efficiently in flies. By studying a range of cell types and examining the role of all gamma-TuRC components, I hope to gain a better understanding of how microtubule nucleation is regulated in space and time throughout animal development.

Amount: £912,868
Funder: The Wellcome Trust
Recipient: University of Cambridge

Protein citrullination in cell physiology and disease. 29 Oct 2014

The post-translational modification (PTM) of proteins is central to the regulation of most cell functions and provides an enormous degree of additional complexity to the proteome. The post-translational conversion of peptidylarginine to citrulline (citrullination) is carried out by a small family of enzymes called peptidylarginine deiminases (PADIs). It is found on proteins of different functional categories and is therefore likely to regulate diverse cellular processes. Importantly, abnormal ci trullination is a feature of various pathological states including autoimmunity, neurodegeneration, atherosclerosis and cancer. It serves as a diagnostic and prognostic marker and its inhibition has shown efficacy in disease models. I recently showed that the nuclear deiminase PADI4 regulates pluripotency and identified a new molecular mechanism by which it mediates chromatin decondensation. Using high resolution proteomics I defined the citrullinome in cell types where PADI4 is functionally r elevant. I will extend this work to define the molecular causes of PADI4 activation and its consequences for pluripotency, self-renewal, DNA methylation and the development of acute myeloid leukaemia. This work will advance the current understanding of citrullination, help to delineate new modes of regulation of cell physiology and disease and may uncover knowledge that is of prognostic, diagnostic and therapeutic value.

Amount: £1,045,097
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Female infertility: deciphering the mechanisms that perturb ERa-signalling in the hypothalamus. 29 Oct 2014

There is an increasing clinical demand for affordable and effective treatments for female infertility associated with obesity and diabetes. However, despite its importance to the health of the population, the mechanistic details of how metabolic pathways affect the female reproductive axis are poorly understood. There are evidence in mice, including my own data, that infertility associated with nutrient deficit is caused by the failure of hypothalamic ER-alpha to appropriately respond to estroge n-stimulation. Decreased leptin signaling has been implicated in this process. However, the molecular details of how this occurs are not known. Therefore, the aim of the proposal is to determine what governs ER-alpha activity during health and disease. I have preliminary data that suggest co-activator and co-repressor interactions play an important role. I will identify co-factors that differentially modulate the activity of ligand-bound ER-alpha in two distinct regions of the hypothalamus to maintain fertility during favorable conditions. The mechanism of action of these co-factors will be determined using in-vitro assays and tissue-specific KO mice. Then, I will assess the importance of these co-factors in regulating female reproduction in models of metabolic-stress, including leptin-treatment. Understanding the dynamics of the functional ER-interactome will inform novel strategies for assisted reproduction therapy.

Amount: £896,976
Funder: The Wellcome Trust
Recipient: Imperial College London

The rise and fall of executive functions: Modelling the neural mechanisms of age-related changes in higher cognitive abilities. 13 Apr 2015

This research aims to determine how changes in prefrontal structure and function affect executive functions across the lifespan. This project attempts to address three challenges that pervade the literature on neurocognitive ageing: Small samples, cross-sectional data and predominantly univariate statistical approaches. This project hopes to overcome these limitations by access to, and close collaboration with, three unique developmental studies: NSPN in London, Cam-CAN in Cambridge and BASE-II at the MPI in Berlin. I will use psychometric models and longitudinal, multimodal neuroimaging to address four key questions. First, I will use Latent Growth Curve Modelling to determine optimal neurodevelopmental trajectories in adolescents. Second, I will use hierarchical MIMIC models to capture the cascade of effects of white matter changes on processing speed and reasoning. Third, I will examine task-based functional connectivity of the prefrontal cortex following prefrontal atrophy to provi de a critical test of the scaffolding hypothesis. Finally, I will use equality-constrained multifactor MIMIC models to determine and compare prefrontal structure and function between healthy and non-healthy cognitive agers. Together, the unique nature of the datasets and novelty of the statistical approaches promise to greatly increase our understanding of neurocognitive development and ageing.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: Medical Research Council

How chemokine signalling and antigen recognition are integrated by T cells. 13 Apr 2015

Integration of diverse signals at the immunological synapse (IS) is fundamental to T-cell responses. Although its structure is well studied regarding the organisation of proteins directing cell-cell interactions, how signalling by G protein-coupled receptors (GPCRs) in general, and chemokine receptors in particular, is integrated at the IS is surprisingly poorly understood. This proposal aims to characterise spatiotemporal chemokine receptor organisation within the IS using confocal and single-m olecule microscopy of four receptors of particular interest. The mechanisms mediating receptor organisation will be elucidated by reconstructing the antigen-presenting cell surface with artificial bilayers, and using interaction-deficient receptor mutants. I will examine the IS-dependency of signal-integration by visualising signalling events therein in the presence and absence of chemokine gradients, and by perturbing normal IS organisation, complementing imaging with biochemical assays. I will also determine which of the 54 Rhodopsin-family GPCRs expressed natively by T cells participate in cellular activation through systematic knock-outs; comprising the first system-level analysis of T-cell GPCR function. This will provide new insights into the extent to which GPCR function is enhanced at IS-like structures and the importance of these structures for lymphocyte cell-cell communication generally. This research also has the potential to identify new immunologically and/or pharmacologi cally active receptors.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Decisions and dopamine in frontal cortical circuits. 19 Nov 2014

This proposal has three aims. Firstly, I will investigate whether the phasic activation of dopamine neurons projecting to different brain structures, namely NAc versus mPFC, could cause distinct effects on perceptual decision making. To do so, I will use optogenetic tools to stimulate dopamine neurons of a mice engaged in visually guided decision task. Secondly, I will study how the projection-pathway specific dopamine activity modulates frontal cortical responses. In doing so, I will record the activity of single neurons in different parts of mPFC while optically stimulating dopamine neurons projecting to different target structures. Finally, I will investigate dopamine-related frontal cortical dynamics underlying perceptual decisions. By combining two-photon microscopy and genetic tools, I will examine the simultaneous activity of several dopamine receptor expressing neurons in mPFC while the mice is engaged in the perceptual decision task. If successful, these studies will support t he proposal that projection-pathway specific and cell-type specific modulation of neuronal circuits shape the decision process. As such, this research will provide important insights about the neurobiology of goal-directed behaviour and will open new directions in the study of cortico-basal ganglia dynamics.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

It's about time: the role of temporal context in adaptive auditory coding. 19 Nov 2014

Encoding the temporal organization of natural acoustic scenes is essential for accurate comprehension of sounds, but research on the role of temporal structure in adaptive auditory coding is lacking. In this proposal, I will investigate the neural mechanisms that govern how temporal context shapes auditory learning and memory. The first project will assess how temporal structure is learned implicitly by decoding of rapid memory formation from population activity in auditory and frontal cortical regions. We hypothesize that memory formation becomes progressively more evident and robust from primary to non-primary auditory cortical areas, and most explicit in frontal cortex. The second project will study explicit learning of temporal structures associated with differential timing of rewards and examine whether timing of rewards during behaviour is encoded by primary auditory cortex. These questions will be addressed in humans using electroencephalography (EEG), which allows access to ens emble responses across multiple cortical regions. In ferrets, the use of planar microelectrode arrays (up to 96 channels) will provide a broad coverage and yield simultaneous responses across primary and non-primary auditory cortex during behaviour. Taken together, this integrative approach will help identify the neural bases of encoding and learning of the temporal structure of natural sounds.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Systematic identification and characterisation of poxvirus lateral body constituents using quantitative proteomics and advanced superresolution microscopy. 19 Nov 2014

The aim of this research program is to elucidate the molecular components of poxvirus lateral bodies and determine their role in the viral life cycle. Poxviruses are large, enveloped, double-stranded DNA viruses characterised by their complex structure and cytoplasmic replication site. All poxviruses, deposit two protein rich structures, termed lateral bodies, into the cell cytoplasm during infection. The development of poxviruses as vaccine vectors and oncolytic agents, as well as on-going zoon otic poxvirus outbreaks and the potential threat of smallpox bioterrorism, warrant continued research on these important pathogens. This study will focus on the prototypic poxvirus, vaccinia. Taking a novel interdisciplinary approach, I will use advanced technologies that allow for high-throughput mass spectrometry identification and then superresolution visualisation of lateral body constituents. This will be followed by characterisation of their roles in the viral life cycle and immunomodulati on using a variety of virology, cell biology, biochemistry, and microscopy technologies. This research will provide detailed understanding of how poxviruses use their lateral bodies to package and then deliver cell modulatory factors into the host cytosol during infection. This will elucidate the function of these poorly understood viral structures and may identify cell- or immune-modulating viral components with powerful potential therapeutic applications.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

Understanding the cytotoxicity of pyocin L1 as a tool for antibiotic development. 19 Nov 2014

This project aims to identify the molecular target through which the lectin-like bacteriocins (LLBs) exert their cytotoxicity, and define its interaction with pyocin L1 and other homologous LLBs. Pyocin L1, which is active against Pseudomonas aeruginosa, is the best characterised LLB and will be used as the model in this study. The three key aims of this project are: Aim 1. Determine the cellular target and mechanism of P. aeruginosa killing by pyocin L1. Aim 2. Characterise the cell enve lope stress response of P. aeruginosa to pyocin L1. Aim 3. Characterise the pyocin L1-target interaction. Aim 1 will use several complementary techniques to determine the genetic basis of resistance to LLBs, identify interaction partners using co-purification techniques and study the interaction of LLBs with live cells, in real-time. Aim 2 will define the global transcriptional response of P. aeruginosa to pyocin L1 and other antibiotics, generating information on the poorly understood env elope stress regulon in P. aeruginosa. Aim 3 will use X-ray crystallography and biophysical techniques to study, in detail, the interaction of pyocin L1 with its cellular target. The interactions of other LLBs with this target or homologous targets will also be studied.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Leveraging genetic variation in the social partners to investigate effects of the social environment on behaviour 19 Nov 2014

I will use laboratory rodents to investigate indirect genetic effects (IGE) of social interactions between cage-mates in the weeks following weaning, a period corresponding to adolescence and early adulthood in humans[21]. My first goal is to characterise the genetic architecture of IGE, namely their contribution to phenotypic variation in the population - which I will compare to that of direct genetic effects (DGE), the number of quantitative trait loci (QTL) underlying IGE and their individu al effect-sizes. To do this, I will analyse three existing datasets comprising hundreds of measures of biomedical relevance and genome-wide genotypes for thousands of mice and rats[22-24]. In these analyses, I will model IGE and DGE jointly in the framework of mixed models[1]. My second goal is to establish whether modelling IGE and DGE jointly improves estimates of DGE and leads to better statistical power to map genetic loci underlying DGE. My third goal is to identify genes, molecular pathw ays, and phenotypes underlying behavioural IGE. I will use a combination of genetic mapping and expression profiling in a controlled experiment designed to maximise power to detect and dissect IGE. In this experiment, the genetic background of all focal mice will be the same and that of cage-mates heterogeneous.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: Embl At Hinxton

We're Stuck!. 17 Jun 2015

This application is to fund the development, creation and performance of a new piece of ground-breaking interactive theatre including 40 performances in London and Manchester. We're Stuck! is an innovative adventure for children aged 8-11, their teachers and parents, inspired by the extraordinary abilities and limitations of our brains when it comes to maths. The show's structure and content will be rooted in the latest educational neuroscience research, drawing on the expertise of neurosc ientists Professor Michael Thomas (Birkbeck), Dr Roi Cohen Kadosh (Oxford), and Professor Matt Nolan (Edinburgh), together with psychologists Professor Andy Tolmie and Dr Emily Farran (UCL Institute of Education). The performance will explore the ways in which our brains are and aren't like computers, with particular reference to ongoing research into spatial navigation. We'll be inspired by the cutting edge of cybernetic research, imagining extraordinary possibilities such as humanoid, neurall y-controlled robots. Created in collaboration with award-winning games designer Sophie Sampson, the show will combine live action games with a gripping story-line to challenge and inspire families. In the company of our team of skilled performers, children will make mistakes, get stuck, struggle with ludicrously difficult tasks and risk total failure. It'll be fun. Supported by Shoreditch Town Hall and Z Arts (Manchester) and produced by China Plate, We're Stuck will promote collaborati on between scientists, artists and education professionals. Together we'll challenge the dominant cultural narratives of maths learning, error and intelligence, and inspire interest and debate around educational neuroscience.

Amount: £39,800
Funder: The Wellcome Trust
Recipient: Misc Greater London

Altered States . 17 Jun 2015

From Moroccan Gnawa musicians to Pentecostal church ceremony to contemporary electronic artists, the relationship between music and altered states of consciousness transcends ethnicity, religion and even culture. The ways in which music affects us on a physiological level is varied and complex. The feelings so familiar, emotions so ingrained in our collective psyches that we very rarely discuss them in a wider context. Altered States is visually arresting new film project, encompassing elemen ts of video essay, experimental documentary, digital art, bespoke live performance and new scientific study aimed at exploring the role that music plays in us as a species - from its function in the evolution of the human species, through to its manifestations in modern society as a powerful cultural identifier as well as its highly effective therapeutic qualities on both individual and mass scales. The desire to use music as a form of escapism and meditation is inherent in us, but through t his film we aim to reveal some uncomfortable truths about how and why we may be stifling the great social and medicinal properties of the musical experience. Collaborating with leading neuroscientists, psychologists, ethnomusicologists, therapists and the musicians and producers who inhabit this world we will tell an experimental, powerful and wide reaching story that will change the very core of how we understand and appreciate music. TASTER VIDEO: http://lucafilms.co/

Amount: £40,000
Funder: The Wellcome Trust
Recipient: Luca Productions Ltd